Although highly active anti-retroviral therapy controls HIV replication and progression to AIDS, it does not actually cure the infection. We are using molecular biology and protein engineering to better understand the mechanisms that allow viral persistence and to develop drugs to combat it. Recently we found, by sequence analysis of the virus induced by pure HIV antigens, that HIV-specific CD4 helper cells provide a fertile milieu for viral replication and evolution due to their unique ability to be activated and infected by the same pathogen. The ability of the very cells that are supposed to fight HIV to promote viral growth has important clinical implication for treatment interruptions and therapeutic vaccines. We have also developed a two-stage strategy to reduce the size of the latent reservoir of HIV that is responsible for viral persistence. The first step of this strategy is to induce the expression of latent infectious virus using synthetic analogues of the lipid second messenger diacylglycerol to activate transcription through the HIV LTR. The second step is to kill the induced cells with a targeted toxin that binds to the viral envelope protein through genetically engineered antibody or fusion sequences. The ability of these reagents to reduce the size of the HIV-1 reservoir is being evaluated in several systems including SCID-hu mice, SIV-infected macaques, and blood cells from infected individuals. Lastly, we are developing live microbial microbicides to protect against HIV infection in resource poor environments.